Age-related macular degeneration (AMD) is a major cause of central visual loss and is the leading cause of blindness in people over the age of 60 in the United States. The National Eye Institute estimates that there are approximately 1.6 million people in the United States with late AMD. (See, e.g., “Vision Problems in the U.S.,” US Dept. of Health and Human Services, Nat'l Institutes of Health, Nat'l Eye Institute, 2002, www.nei.nih.gov.)
AMD is a complex disease whose risk factors include aging, family history of AMD, smoking, hypertension, obesity, diet, and ethnicity, and there is a strong indication of a genetic contribution. Ambati et al., Surv. Ophalmol., 48:257 (2003). Two major clinical phenotypes of AMD are recognized: a nonexudative (thy) type and an exudative (wet) type.
The dry form of AMD is associated with cell death of the light-sensitive macular part of the retina, which is required for fine vision used in activities such as reading, driving or recognizing faces. Over time, as less of the macula functions, central vision in the affected eye can be lost gradually. One of the most common early signs of dry AMD is the appearance of drusen. Drusen are yellow deposits under the retina and are often found in people over the age of 60. Dry AMD has three stages, all of which may occur in one or both eyes: early AMD, intermediate AMD, and advanced AMD. Early and intermediate AMD are characterized by the presence of small or medium-sized drusen, and persons suffering from early and intermediate AMD may require additional light when reading and experience a blurred spot in the center of their vision. Persons suffering from advanced AMD, in addition to the presence of medium or large-sized drusen, exhibit a breakdown of light-sensitive cells and supporting tissue in the central retinal area.
The wet form of AMD is caused by growth of abnormal blood vessels, also known as choroidal neovascularization (CNV), under the macula. These vessels leak blood and fluid which raises the macula from its normal position at the back of the eye and causes scar tissue formation, which destroys the central retina and results in deterioration of sight. The pathogenesis of new choroidal blood vessel formation which characterizes wet AMD is not completely understood. Inflammation, ischemia, and local production of angiogenic factors are all thought to be important in pathogenesis. With wet AMD, loss of central vision can occur quickly. Wet AMD is considered to be advanced AMD and is more severe than the dry form.
The dry form of AMD is more prevalent; about 85% of all people with intermediate and advanced AMD have the dry form. However, about two-thirds of all patients with advanced AMD have the wet form. It is believed that all patients who have the wet form of AMD had the dry form first. (See, “Age-Related Macular Degeneration: What You Should Know,” US Dept. of Health and Human Services, Nat'l Institutes of Health, Nat'l Eye Institute, Publn. No. 03-2294, 2003.)
Although the direct cause of AMD remains unknown, recent studies have pointed to a number of single nucleotide polymorphisms (SNPs) in and around the gene for complement Factor H which appear to predispose people to AMD. Patients exhibiting this mutation have been linked to an increased likelihood of developing the disease. See, Hageman et al., 2005, PNAS, 102(20): 7227-7232; Klein et al., 2005, Science, 308: 385-388; Haines et al., 2005, Science, 308: 419-421. See, also, Edwards, 2005, Science, 308: 421; Li, 2006, Nature Genetics, 38: 1049; Despriet, 2006, JAMA, 296: 301; Mailer, 2006, Nature Genetics, 38: 1005.
Factor H is one of the complement regulatory proteins which down-regulates complement activation and is a member of the family of genes known as the Regulators of Complement Activation (RCA) gene locus encoded on human chromosome 1q32. The complement system is a group of proteins that constitutes about 10 percent of the globulins in normal serum of humans (Hood et al., Immunology, 2d Ed. (The Benjamin/Cummings Publishing Co., Menlo Park, Calif., 1984), p. 339), and it plays an important role in the mediation of immune and allergic reactions. The complement system is a major component of innate immunity and is a central host defense against infection. The activation of complement components leads to the generation of a group of factors, including chemotactic peptides that mediate the inflammation associated with complement-dependent diseases.
Activation of the complement cascade may occur via the classical pathway, involving antigen-antibody complexes; by the lectin pathway, or by the alternative pathway, involving the recognition of certain cell wall polysaccharides. The activities mediated by activated complement proteins include lysis of microorganisms, chemotaxis, opsonization, stimulation of vascular and other smooth muscle cells, degranulation of mast cells, increased permeability of small blood vessels, directed migration of leukocytes, and activation of B lymphocytes and macrophages. The membrane attack complex (MAC) is the final product of the activated complement cascade. It is a lytic multi-protein complex that is lethal to pathogens and, at sublytic levels, causes the release of cytokines and growth factors such as beta-FGF and VEGF from nucleated cells (e.g., smooth muscle cells, endothelial cells).
Factor H is one of a dozen or so proteins of the complement system having a repeating structural motif known as a short consensus repeat (SCR) and sharing a capacity for interacting with activation products of the complement components C3 and C4, as well as other components of the complement system. Ahearn et al., 1989, Adv. Immunol., 46:183-219. During complement activation, biologically active peptide fragments, the anaphylatoxins C3a, C4a, and C5a, are released from complement components C3, C4, and C5. Hugh, 1981, CRC Crit. Rev. Immunol., 1:321. Factor H and other complement regulatory proteins such as C4-binding protein (C4-BP), decay accelerating factor (DAF), membrane cofactor protein (MCP), and complement receptor type I (CR1) have a negative regulatory activity and are able to block one or both of the complement activation pathways.
Current treatments for AMD are limited. No treatment for advanced dry AMD exists. However, the transition from intermediate AMD to advanced AMD can be delayed and possibly prevented by taking a specific high-dose formulation of antioxidants and zinc. Research has shown that a daily intake of supplements, including: vitamin C (500 milligrams); vitamin E 400 IU; beta-carotene (15 milligrams); zinc (as zinc oxide) (80 milligrams); and copper (as cupric oxide) (2 milligrams), reduced the risk of patients advancing from intermediate AMD to advanced AMD by 25%, and reduced the risk of vision loss by 19%. (www.amd.org).
Currently there are only four treatments approved by the FDA for wet AMD: laser surgery, photodynamic therapy (PDT), and the drugs Macugen® pegaptanib sodium and Lucentis™ ranibizumab intravitreal injections. Laser, PDT and pegaptanib may slow the rate of vision decline and/or stop vision loss. Pegaptanib (Macugen®, Eyetech Pharmaceuticals Inc. and Pfizer Inc.), is approved for treatment of wet AMD is a pegylated oligonucleotide aptamer targeting VEGF. Ranibizumab (Lucentis™, Genentech/Novartis), an antibody fragment targeting VEGF, has recently been approved by FDA for the treatment of wet AMD.
Laser surgery attempts to destroy the fragile, leaky blood vessels using a high energy beam of light. This treatment, however, may also destroy some surrounding healthy tissue and therefore actually contribute to further vision loss. Because of this, only a small percentage of people with wet AMD can be treated with laser surgery.
Photodynamic therapy also attempts to destroy the newly formed blood vessels in the patient's eye. Verteporfin (marketed in the US by Novartis under the name Visudyne®) is injected into the patient's arm. The drug travels through the patient's body, “sticking” to the surface of new blood vessels. A light is then shone in the patient's eye, which activates the drug, which in turn destroys the new blood vessel. Photodynamic therapy merely temporarily slows the rate of vision loss; it does not stop vision loss or restore vision. Moreover, because the drug is activated by light, the patient must avoid sunlight and bright indoor lights for five days after treatment.
Genetic research continues to illuminate more treatment options. For example, in a study released in September 1997, scientists reported that 16% of 167 patients with dry AMD had a defect in a gene called ABCR. See, Allikmets et al., 1997, Science, 277(5333): 1805-7. However, the fact that 84% of the patients suffering from dry AMD in the study did not have the ABCR gene defect indicates that further research is needed. Other family-based whole-genome linkage scans have identified chromosomal regions that show evidence of linkage to AMD; however, the linkage areas have not been resolved to any causative mutations. See, Klein et al., 2005, Science, 308: 385-388.
While the recent studies linking a mutation in a complement regulatory protein (Factor H) to development of AMD (see, Hageman et al., 2005, supra; Klein et al., 2005, supra; Haines et al., 2005, supra; Edwards et al., 2005, supra) raises the question of whether the function of Factor H in regulating complement activation is one factor that might play a role in AMD, there is as yet no evidence that therapeutic administration of complement proteins has any impact on AMD. No treatment or therapy utilizing components of the complement system has been proposed.
Clearly, needs remain for an effective treatment of age-related macular degeneration and like diseases of the eye characterized by undesired or abnormal neovascularization.